Excessive immune responses to external or internal factors may lead to disease, which may be characterized as Th1- or Th2-mediated diseases. Asthma, allergic rhinitis (hay fever), atopic dermatitis (eczema) and food allergies, examples of Th2-mediated diseases, are exceedingly prevalent, affecting 20-40% of the general population and constituting a major public health problem. The economic costs for these disorders are enormous. For asthma alone, the estimated health care costs in 1996 were
14 billion. In addition, the prevalence of all of the atopic diseases has increased dramatically in industrialized countries over the past two decades for reasons that are not yet clear. The prevalence of asthma in industrialized countries, for which the numbers are the most accurate, has doubled since 1982, and is projected to double again in prevalence by the year 2020.
Rheumatoid Arthritis (RA), a Th1 disorder, is a common human autoimmune disease with a prevalence of about 1% among Caucasians (Harris, B. J. et al., 1997, In Textbook of Rheumatology 898-932), currently affecting 2.5 million Americans. RA is characterized by chronic inflammation of the synovial joints and infiltration by activated T cells, macrophages and plasma cells, leading to a progressive destruction of the articular cartilage. It is the most severe form of joint disease. Multiple Sclerosis (MS), another Th1 disorder, is the most common central nervous system (CNS) demyelinating disease, affecting 350,000 (0.1%) individuals in North America and 1.1 million worldwide. In general, MS is considered to be an autoimmune disease mediated in part by proinflammatory CD4 T (Th1) cells that recognize specific myelin polypeptides in association with MHC class II molecules expressed on antigen (Ag) presenting cells (APC). Another example of a Th1 mediated disorder, human type I or insulin-dependent diabetes mellitus (IDDM), is characterized by autoimmune destruction of the beta cells in the pancreatic islets of Langerhans. The depletion of beta cells results in an inability to regulate levels of glucose in the blood. In humans a long presymptomatic period precedes the onset of diabetes. During this period there is a gradual loss of pancreatic beta cell function. The development of disease is implicated by the presence of autoantibodies against insulin, glutamic acid decarboxylase, and the tyrosine phosphatase IA2 (IA2).
T helper (Th) subsets are distinguished by their ability to produce distinct cytokine patterns and promote specific immune responses. Th1 cells produce IFNγ and promote cell-mediated immunity directed towards intracellular pathogens. In contrast, Th2 cells produce the cytokines IL-4, IL-5, and IL-13, activate mast cells and eosinophils and direct B cells against extracellular pathogens.
The specific cytokines produced by polarized Th cells are the primary effectors that promote differentiation of precursor Th cells, but these cells also cross-regulate the other subset's functional activity. For example IL-4 is reported to be a potent factor in promoting the differentiation of Thp cells to Th2 effectors. In addition, IL-4 antagonizes production of IFNγ. IL-10, another cytokine produced by Th2 cells, has also been described to inhibit Th1 development and IFNγ-induced macrophage function. Conversely, the IFNγ produced by Th1 cells amplifies Th1 development and inhibits the expansion of Th2 cells. The ability of these cytokines to promote development of specific Th cell subsets, while simultaneously inhibiting the alternate developmental fate, results in a progressively polarized response.
Accordingly, a need exists for novel therapies which promote or inhibit the development of Th1 or Th2 responses. Such novel therapies my be used to treat autoimmune and allergic diseases, to enhance immune tolerance of transplanted tissues or to decrease immune tolerance in individuals afflicted with cancer.